NF-κB prevents β cell death and autoimmune diabetes in NOD mice

Abstract

Whereas NF-κB has potent antiapoptotic function in most cell types, it was reported that in pancreatic β cells it serves a proapoptotic function and may contribute to the pathogenesis of autoimmune type 1 diabetes. To investigate the role of β cell NF-κB in autoimmune diabetes, we produced transgenic mice expressing a nondegradable form of IκBα in pancreatic β cells (RIP-mIκBα mice). β cells of these mice were more susceptible to killing by TNF-α plus IFN-γ but more resistant to IL-1β plus IFN-γ than normal β cells. Similar results were obtained with β cells lacking IκB kinase β, a protein kinase required for NF-κB activation. Inhibition of β cell NF-κB accelerated the development of autoimmune diabetes in nonobese diabetic mice but had no effect on glucose tolerance or serum insulin in C57BL/6 mice, precluding a nonphysiological effect of transgene expression. Development of diabetes after transfer of diabetogenic CD4⁺ T cells was accelerated in RIP-mIκBα/nonobese diabetic mice and was abrogated by anti-TNF therapy. These results suggest that under conditions that resemble autoimmune type 1 diabetes, the dominant effect of NF-κB is prevention of TNF-induced apoptosis. This differs from the proapoptotic function of NF-κB in IL-1β-stimulated β cells.